Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis

Somatic mutation is now recognized as a cause of multiple human diseases other than cancer. Osteoarthritis (OA), a highly prevalent age-related disease, has been associated with increased chromosomal abnormalities in articular cartilage. Here we characterize the somatic mutational landscape of chondrocytes during normal aging and in affected cartilage of patients with OA. We used single-cell whole-genome sequencing to analyze single-nucleotide variants (SNVs) and small insertions and deletions (InDels) in 100 chondrocytes isolated from the cartilage of hip femoral heads of 17 research participants aged 26−90 years, including 9 patients with OA and 8 non-OA donors. Both SNVs and InDels accumulate with age in chondrocytes with a clock-like mutational signature. Surprisingly, the age-related accumulation rate in OA chondrocytes is lower than that in non-OA control chondrocytes. Differences in mutational signatures and Gene Ontology term enrichment were found between OA and non-OA control samples. In this study, to understand the role of somatic mutation in the pathogenesis of OA, we characterized somatic SNV and InDel mutations. With further progress in analytical approaches, structural variations in the chondrocyte genome are also expected to provide valuable information. Somatic mutations accumulate with age and have been linked to functional decline and disease. Single-cell analysis of human cartilage samples from donors with and without osteoarthritis shows that somatic mutations accumulate with age, but, in osteoarthritis, they show distinct mutational patterns and slower accumulation, possibly due to DNA-damage-induced chondrocyte death.